Microtubule Dynamics and Chromosome Segregation

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DESCRIPTION (provided by applicant): During cell division the capture of dynamic microtubules by the centromere initiates chromosome movement and, ultimately, the segregation of chromosomes to each daughter cell with high fidelity.Chromosome movement involves the coordination of microtubule motor activity and microtubule polymerization dynamics. Many anti-cancer drugs disrupt cell division by suppressing microtubule dynamics. In cells, the dynamic behavior of microtubules is modulated by accessory factors such as the Kin I family of microtubule motors. These kinesin-related proteins have evolved the ability to depolymerize microtubules rather than walking along the surface lattice of the microtubule to transport cargo. The centromere is the engine for chromosome movement and is responsible for coordinating chromosome movement with microtubule dynamics. The long-term objective of this proposal is to determine how the centromere segregates chromosomes with high fidelity. The centromere is able to modulate the dynamic behavior of the microtubule ends to which it attaches. Previously we have identified a centromere-associated member of the Kin I family of microtubule motors, which is most likely to be responsible for modulating microtubule dynamics in conjunction with chromosome movement. Specifically we will test how the regulation and spatial localization of the ATP-dependent microtubule depolymerizing activity of Mitotic Centromere-associated Kinesin (MCAK) contributes to the accurate segregation of chromosomes during mitosis. To perform this study it is essential to (1) understand the mechanism by which MCAK depolymerizes microtubules, (2) determine if MCAK's microtubule depolymerizing activity is modulated by regulatory factors during cell division and, (3) determine the precise role that MCAK plays in ensuring chromosome segregation with high fidelity. By answering these questions regarding MCAK function and regulation we will make great strides in understanding how the stability of the genome is maintained over the lifetime of an organism. MCAK has been identified as a gene, which is up-regulated in certain kinds of proliferative tumors. Therefore, in the course of these studies we will uncover information and produce tools that may be important in the diagnosis or in understanding the etiology of these types of tumors.